Cancer is an uncontrolled growth and spread of cells that may affect almost any tissue of the body. Cancer can be defined as abnormal growth of tissues characterized by a loss of cellular differentiation. It is caused due to a deregulation of the signaling pathways involved in cell survival, cell proliferation and cell death.
Current treatments for cancer and related diseases have limited effectiveness and a number of side effects. Cancer therapy currently falls under the following categories including surgery, radiation therapy, chemotherapy, bone marrow transplantation, stem cell transplantation, hormonal therapy, immunotherapy, antiangiogenic therapy, targeted therapy, gene therapy and others.
In the treatment of cancer, chemical compounds are used to reduce, inhibit, or diminish the proliferation of tumor cells, and thereby assist in reducing the size of a tumor. These compounds, which exhibit antitumor activity, find use in the treatment of cancers.
Chronic myeloid leukemia (CML) is a type of cancer characterized by the clonal proliferation of malignant myeloid progenitor cells resulting in excessive number of myeloid cells in all stages of maturation. Development of CML is associated with a specific chromosomal translocation known as the Philadelphia (Ph) chromosome. A molecular consequence of this translocation is the generation of a fusion protein Bcr-Abl, a constitutively activated tyrosine kinase that is detectable throughout the course of the disease. The Ph chromosome produces an enzyme, a fusion protein (Bcr-Abl) that plays a central role in aberrant cell growth and division. This aberrant enzyme sends out signals through multiple pathways within the cell, resulting in the overproduction of white blood cells in the body. The result is that, while a healthy cubic millimeter of blood contains 4,000 to 10,000 white blood cells, blood from a patient with CML contains 10 to 25 times this amount. The massive increase in the number of white blood cells characterises CML. In addition to CML, acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) are Ph positive leukemias.
The median survival of patients after diagnosis with CML is 4-6 years, with a range of less than one year to more than 10 years (National Cancer Institute: Chronic Myeloid Leukemia: Treatment: Health Professional Version: General Information 2006). Treatment options for patients with CML are limited and are based on the stage of leukemia, and the patient's age and health. The disease may be treated with bone marrow transplant (BMT) therapy or with drug therapy. Interferon-alpha has been used for the treatment of CML and has shown improved survival in CML patients. However, there are reports of patients showing resistance to the treatment with Interferon-alpha (Leukemia Research, 2003, 27, 5, 405-411).
Recent reports have shown that ectopic Bcr-Abl expression dramatically increases TGFβ/Smad-dependent transcriptional activity in Cos1 cells, and that this may be due to enhancement of Smad promoter activity (FEBS Letters, 2007, 581, 7, 1329-1334; Leukemia, 2007, 21, 494-504). Bcr-Abl expressing TF-1 myeloid cells are more potently growth arrested by TGFβ compared to the parental TF-1 cell line. The expression of Bcr-Abl leads to hyper-responsiveness of myeloid cells to TGFβ, and that this novel cross-regulatory mechanism might play an important role in maintaining the transformed progenitor cell population in CML. A small pocket of haemopoietic stem cells, which are resistant to imatinib mesylate, in part because they are non-cycling, also hinders the complete eradication of CML. Therefore, TGFβ is a prime candidate for maintaining these CML stem cells in a non-cycling state. An upregulation or prolongation of TGFβ signaling by Bcr-Abl, suggests that one of the mechanisms by which Bcr-Abl promotes the transformation of haemopoietic progenitor cells, is by influencing the level of TGFβ signaling activity. TGFβ plays a vital role in the preservation of the malignant progenitor population, and is partially responsible for the resistance to treatments targeting Bcr-Abl that is observed in a proportion of CML patients.
CRKL protein [V-crk sarcoma virus CT10 oncogene homolog (avian)-like] belongs to the SH2-SH3 family of adaptor proteins. It is a 39-kD protein and is constitutively heavily phosphorylated in Philadelphia-chromosome positive CML cells. It is a prominent substrate for Bcr-Abl kinase. It is also stably phosphorylated in neutrophils from patients in chronic phase of CML at a point in maturation when the Bcr-Abl kinase activity is downregulated as measured by autophosphorylation. CRKL and Bcr-Abl form a complex suggesting a significant role for this adaptor protein in Bcr-Abl transformation. Phospho-CRKL monitoring has been recognized as a prognostic marker in CML patients treated with first and second generation Bcr-Abl inhibitors (Haematologica, 2008, 93, 5, 765-769; The Journal of Biological Chemistry, 1994, 269, 37, 16, 22925-22928).
Imatinib mesylate (Gleevec® or Glivec®; Novartis India Ltd.) is currently the most specific drug for the treatment of CML and is regarded as a very effective therapy. Imatinib mesylate inhibits the Bcr-Abl tyrosine kinase and the effectiveness of imatinib mesylate in CML patients is based on overall hematologic and cytogenetic response rates. Despite significant hematologic and cytogenetic responses, resistance to imatinib mesylate has also been observed in CML patients, particularly in patients who have progressed to either the accelerated or blastic phase of the disease. U.S. Pat. No. 7,521,175 describes possible mechanisms associated with imatinib mesylate resistance in CML patients and discloses a number of Bcr-Abl mutants associated with resistance to imatinib mesylate. Attempts have been made to find new therapeutic strategies to prevent or overcome this resistance.
Recently, two experimental drugs namely nilotinib (AMN-107; Novartis India Ltd.) and dasatinib (BMS-354825; Bristol Myers Squibb) were found to be effective in circumventing some but not all forms of imatinib mesylate resistance (Expert Reviews, Anticancer Ther., 2008, 8, 9, 1387-1398). The T315I mutant is one of the more predominant mutations seen in imatinib mesylate-resistant patients. This T315I mutation was shown to preserve kinase activity resulting in ineffective binding of imatinib mesylate to Bcr-Abl. Another drug, Homoharringtonine (ChemGenex Pharmaceuticals) which is in the Phase II/III stage has been found to be useful for patients with imatinib mesylate resistant CML, including those containing the T315I mutation (Expert Reviews, Anticancer Therapy, 2008, 8, 9, 1387-1398). However, despite these developments, there still exists a continuing need for agents which are effective against the imatinib mesylate-resistant CML.
Blood, 2003, 101, 690-698, describes the K-562-R resistant cell line. K-562 is one of the human leukemic cell lines which contains a wild type Bcr-Abl protein, while K-562-R is a K-562 cell line which is made resistant to imatinib mesylate by continuous exposure to imatinib mesylate (2 μg/mL).
Cancer Research, 2005, 65, 11, 4500-4505 describes various imatinib mesylate resistant cell lines-Ba/F3 Bcr-Abl/T315I, Ba/F3 Bcr-Abl/E255K, Ba/F3 Bcr-Abl/H396P, Ba/F3 Bcr-Abl/M351T, Ba/F3 Bcr-Abl/F359V, Ba/F3 Bcr-Abl/E255V, Ba/F3 Bcr-Abl/F317L, Ba/F3 Bcr-Abl/H396R, Ba/F3 Bcr-Abl/M244V, Ba/F3 Bcr-Abl/Q252H, Ba/F3 Bcr-Abl/Y253F and Ba/F3 Bcr-Abl/Y253H.
Cancer Letters, 1996, 108, 211-214, describes the inhibitory effect of caffeic acid phenethyl ester on human leukemia HL-60 cells.
PCT publication WO2008026125 describes the use of caffeic acid and its derivatives for the treatment of CML, which is resistant to treatment with imatinib mesylate.
There is an urgent need for medicaments for treating cancer, in particular chronic myeloid leukemia (CML) and more particularly, chronic myeloid leukemia that is resistant to treatment with imatinib mesylate due to Bcr-Abl mutation.